Barata, Pedro C.

4568 Background: The 2IR immune response score was initially developed using bulk RNA sequencing of pre-treatment tissue from ImVigor 210 and CheckMate 275 trials, however these trials enrolled patients (pts) with pure urothelial carcinoma (pUC) histology. Patients with hsUC often exhibit worse response to immune checkpoint inibitors (ICI) than patients with pUC. Here, we evaluated the 2IR score as a prognostic or predictive biomarker in real-world pts with hsUC. Methods: Specimens from pts with pUC (n = 1677) and hsUC (n = 417) were profiled at Caris Life Sciences (Phoenix, AZ) using next generation sequencing (NGS) of DNA and RNA. HsUC histologies included majority ( > 50%) squamous (n = 340), sarcomatoid (n = 51), neuroendocrine (n = 20), and micropapillary (n = 6) component. 2IR was calculated by comparative RNA expression of 10 adaptive immune genes and 39 pro-tumorigenic genes. Tumors were classified as 2IR-Low (2IR ≤ -0.5), -Mid (-0.5 < 2IR < 0), and -High (2IR ≥ 0), as previously described (Wang et al., 2022). Spearman correlation analysis was utilized to compare 2IR with tumor mutation burden (TMB), interferon score (IFN) and the tumor microenvironment (TME) cell fractions estimated using quanTIseq. Clinical outcomes included real-world overall survival (rwOS) from ICI start to last contact and time on treatment (ToT) with pembrolizumab, obtained via matched insurance claims data and calculated using Kaplan-Meier methods, while Hazard ratio (HR) was calculated by Cox proportional model. Results: For patients with hsUC, distribution of 2IR score was High 5.76%, Mid 33.3%, and Low 60.9%. Median 2IR score was significantly lower in squamous (-0.60, p < 0.0001) and sarcomatoid UC (-0.82, p < 0.0001) compared to pUC (-0.41) and significantly higher in neuroendocrine UC (-0.15, p = 0.003). Among patients with hsUC, median rwOS was significantly longer for patients with high/mid 2IR score compared to low 2IR score (25.3 [10.9-39.3] months vs. 8.7 [6.2-11.3] months; HR 0.52, 95% CI 0.34 – 0.78, p = 0.0017). ToT with pembrolizumab was also significantly longer for high/mid 2IR score compared to low 2IR score (3.0 [1.4-5.5] months vs. 2.1 [1.4-3.3] months; HR 0.68, 95% CI 0.46-1.00, p = 0.0471). Similar to pUC, 2IR score in patients with squamous UC was positively associated with CD8 T cell infiltration (r = 0.39; p < 0.0001), IFN score (r = 0.41, p < 0.0001), and TMB (r = 0.20, p < 0.001) and negatively associated with M1 macrophage infiltration (r = -0.25, p < 0.0001). 2IR scores in hsUC correlated positively but not significantly with mutations in TP53 (Median: -0.59 vs -0.62, p = 0.067) and PIK3CA (Median: -0.56 vs -0.61, p = 0.172) and negatively with mutations in CDKN2A (Median: -0.67 vs -0.59, p = 0.052). Conclusions: In a real-world cohort of patients with hsUC, we show the 2IR score may be prognostic for rwOS and predictive for pembrolizumab ToT. Prospective studies are needed to further validate this biomarker for use in this population.

4545 Background: The treatment landscape of front-line nccRCC has evolved with recent trials demonstrating the efficacy of combination systemic therapy. However, the efficacy of treatment after combination therapy is unknown. This study evaluates the efficacy of VEGF-based regimens in nccRCC patients (pts) previously treated with combination regimens. Methods: ORACLE is a real-world, multi-center, retrospective database that includes nccRCC patients that received combination systemic therapies (IO+IO, IO+VEGF and VEGF+ mTOR) in any line. Subsequent treatments were categorized as VEGF only regimens (cabozantinib vs other VEGF), IO+ VEGF and VEGF+ mTOR. The primary endpoint was objective response rate (ORR) assessed by investigator review using RECIST 1.1. Secondary endpoints included disease control rate (DCR), defined as the proportion of patients achieving complete or partial responses or stable disease, time to treatment progression (TTP), calculated from the date of VEGF-based initiation to progression or last follow-up using the Kaplan-Meier method. Differences between groups were estimated with the log-rank test, and categorical outcomes were compared with the chi-square test. Results: 105 pts who received VEGF – based regimens after combination therapy were included in the analysis. Baseline characteristics: median age: 59years, 71 % male, 58% white, 25% black, 87% ECOG 0-2. IMDC-risk categories included:21% favorable, 59% intermediate and 20% poor risk. Histology included papillary (40%), unclassified (32%), chromophobe (16%) and other rare subtypes (12%). Prior combination therapies included IO+IO: 62%, IO+ VEGF: 34% and VEGF+ mTORi:4%. 70% pts received combination therapy in the first line setting while the remainder received combination therapy in a second or later line. Outcomes with subsequent treatments are described in Table1. IMDC risk score correlated with TTP. Conclusions: Modest antitumor activity was observed with VEGF- based approaches in combination therapy refractory nccRCC. Optimal management of nccRCC remains an unmet need. Outcomes of nccRCC patients by treatment and histologic type. Outcomes per Treatment n ORR (%) DCR (%) mTTP (mo.) Cabozantinib 56 18 47 3.6 VEGF/mTOR 19 16 42 9.3 IO+VEGF 17 29 47 5.6 Other VEGF 13 15 46 5.5 Outcomes per Histology Papillary 42 19 43 6.5 Unclassified 33 21 42 6.1 Chromophobe 17 29 59 8.9 Other * 13 0 46 NR

387 Background: Level 1 evidence supports treatment of high-risk and node positive PCa using 4-9 weeks of radiotherapy (RT) combined with 18-36 months of androgen deprivation therapy (ADT) with or without abiraterone acetate plus prednisone (AAP). While effective, some cancers recur, and this prolonged treatment is associated with inconvenience and variable morbidity. We aimed to determine whether the biological synergy of stereotactic body radiotherapy (SBRT) with a 6-month combination of ADT, AAP, and the PARP inhibitor niraparib, could enable a shorter intensified, yet safe and effective, therapeutic alternative. Methods: ASCLEPIuS (NCT04194554) is a multicenter investigator-initiated phase I/II trial in high-risk or node positive, homologous recombination unselected, PCa. Patients received 6 months of ADT, AAP, niraparib and SBRT to the prostate (37.5-40 Gy) +/- pelvic lymph nodes (25 Gy). Focal prostate/nodal boosting was permitted. The phase I primary endpoint was the maximum tolerated dose (MTD) of niraparib using the time-to-event continuous reassessment method (3 dose levels: 100 mg and 200 mg held during SBRT, or 200 mg concurrent with SBRT). Dose limiting toxicities (DLT) were any persistent grade 4+ hematologic toxicity or any grade 3+ rectal/urinary toxicity at least possibly related to treatment as assessed by CTCAE v5.0. Patient reported quality of life (QOL) was assessed with the EPIC-26 short form. Linear mixed models were used to compare scores over time. Results: Accrual began in Nov. 2020 with a transition from phase I to phase II in May 2023 after enrolling 54 men. Median follow-up of the phase I cohort is 12.1 months (IQR 9.4-18.9), 80% (n=43) had Grade Group 4-5, median PSA was 17 ng/mL (range, 1-73), 15% (n=8) had cN+ disease, and 76% (n=41) received nodal RT. There were 0 DLTs to date, no grade 3+ rectal or urinary toxicities, and 5 serious adverse events at least possibly attributable to study treatment (anemia, non-rectal gastrointestinal, syncope, infection, musculoskeletal). The most common grade 3 toxicities were hypertension (n = 11, 21%) and leukopenia (n=6, 11%). Transient dose reductions or holds of AAP or niraparib occurred in 10 and 11 patients, respectively. There were no statistically significant declines in patient reported urinary QOL at 6- or 12-months post-treatment compared to baseline (all p >0.15). A transient decline in bowel QOL at 6-months occurred (p<0.01), which improved by 12-months (p=0.16). Conclusions: Our phase I findings support the short-term safety and tolerability of the combination of SBRT to the prostate and nodes, ADT, AAP, and niraparib at an MTD of 200 mg in men with high-risk or node positive PCa. Our trial completed phase II enrollment in May 2024, and longer-term safety, efficacy, and genomic correlations will be presented in the future. Clinical trial information: NCT04194554 .

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

4580 Background: ICIs are used for UC in different settings. Most cases have pure urothelial carcinoma (PUC) but about a third have UC mixed with SH. We examined pts with UC treated with ICI and hypothesized that outcomes would not differ between PUC and mixed with SH. Methods: We retrospectively included pts with PUC and any SH component treated with ICI as adjuvant, 1st line [1L] upfront, maintenance avelumab [mAV], ≥2nd line [2+L] therapy; pts were divided by SH type. Pts with multiple SH were included as separate group. We excluded pts with pure non-UC histology and pts treated with neoadjuvant ICI. We calculated overall response rate (ORR), median overall, progression-free and disease-free survival [mOS, mPFS, mDFS] using KM method from ICI start. Analysis was stratified by therapy line; multivariable models were adjusted by Khaki factors for 1L/upfront, mAV and Bellmunt factors for 2+L; reference group was PUC. We used descriptive statistics for small subsets. Results: We included 1525 pts from 26 sites; n=752 1L, n=609 2+L; 76% men, 80% White, 69% smoking history, 80% lower urinary tract primary, 28% SH. Median f/u time from 1L ICI start 24 months (mo): mPFS was 3 (95%CI 2.8-3.2) mo for PUC (n=340), 3 (95%CI 2-4) mo for squamous (n=60) (HR=1, [95%CI 0.7-1.4]), 2 (95%CI 1.4-3.2) mo for micropapillary (n=36) (HR=1.3 [95% 0.9-2]) and 4 (3.5-4.5) mo for ≥2 SH (n=20) (HR=0.9 [95%CI 0.6-1.5]). Median f/u time from 2+L ICI start 26 mo: mPFS was 3 (95%CI 2.4-3.2) mo for PUC (n=264), 4 (95%CI 2-5) mo for squamous (n=33) (HR=0.8, [95%CI 0.6-1.2]), 3 (95%CI 1.6-3.7) mo for micropapillary (n=17) (HR=0.9 [95% 0.6-1.7]) and 3 (2.5-3.1) mo for ≥2 SH (n=10) (HR=1.2 [95%CI 0.6-2.2]); Table shows ORR/OS data. Data on adjuvant and mAV settings will also be presented. Conclusions: We found no significant survival difference between PUC and SH. ORR was numerically higher with sarcomatoid SH and ≥2 SH in the 1L upfront setting. Limitations: retrospective design, small sample size in a few subsets, lack of randomization and central scan/path (% SH) review, selection bias, unmeasured confounders. [Table: see text]

654 Background: MSI and TMB correlate with ICI efficacy. We assessed the association between TMB and MSI with outcomes in pts with aUC treated with anti-PD1/L1 in a ‘real-world’ cohort. We hypothesize that pts with high TMB and MSI-high (H) have better outcomes with ICI. Methods: In this retrospective study we included pts from 13 sites treated with ICI for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using KM method from ICI start. TMB and MSI were assessed by NGS. TMB was analyzed as dichotomous (≥10 vs <10 mut/Mb) and continuous variable. The analysis was stratified by therapy line (1L/upfront, 2+L). Multivariable models were adjusted by Khaki factors for 1L/upfront and Bellmunt factors for 2+L. We separately analyzed pts on maintenance avelumab (mAV). MSI is reported with descriptive statistics only. Results: 342 pts were treated with ICI 1L/upfront or 2+L (69% pure UC, median age at ICI start 69, 77% men, 90% White, 16% upper tract primary, 12% liver metastases [mets], 78% ECOG PS 0-1). Median f/u from ICI start was 34 months (mo). ORR was 36% (95%CI 26-46%) in pts with TMB≥10 vs 30% (95%CI 23-36%) with TMB<10 (OR=1.4 [95%CI 0.8-2.5] p=0.3). ORR was 75% (6/8) in pts with MSI-H and 30% (60/200) with MSI stable (MSI-S). mPFS was similar between TMB≥10 and <10 groups (6 vs 4 mo; HR=0.88 [95%CI 0.61-1.26] p=0.48) and between MSI-H and MSI-S (5 mo). mOS was numerically longer (not significant) in pts with TMB≥10 vs TMB<10: 25 vs 21 mo; (HR=0.7 [95%CI 0.50-1.09] p=0.12) and with MSI-H and MSI-S (NR and 20 mo). A significant association was found between TMB (continuous variable) and OS (HR=0.97 [95%CI 0.95-0.99] p=0.01). TMB analyses by therapy line are shown in Table. In the 1L/upfront setting (N=144), ORR 71% (5/7) vs 33% (45/135), mPFS 5 and 4 mo, mOS NR and 22 mo for MSI-H and MSI-S, respectively. Pts on mAV (n=77) were 77% men, 92% White, 16% upper primary, 13% liver mets, 84% ECOG PS 0-1 with median f/u 15 mo from avelumab start; mOS was NR for MSI-H and 24 mo for MSI-S; mPFS was 4 mo for both groups. Of 3 pts on mAV with MSI-H: 1 CR, 2 SD; of 58 pts with MSI-S: 4CR, 4PR, 24 SD, 21 PD, 5 unknown. Conclusions: MSI-H had numerically higher ORR and higher TMB was associated with longer OS with ICI, but further validation is needed. Limitations: retrospective design, small sample size for MSI-H cases, lack of randomization and central scan review, selection/confounding. [Table: see text]

Abstract Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44–4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. Significance: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.

MSI-H identified by ctDNA: prevalence across 21 advanced cancers and outcomes from >700 patients.

Abstract Background Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. Methods This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. Results Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node–only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. Conclusions Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

5071 Background: Best treatment of mCSPC involves doublet therapy (ADT + novel hormonal agent) or triplet therapy (ADT + novel hormone + docetaxel); however, opportunity remains for further improvement. Studies show that homologous recombination repair (HRR) gene mutations are enriched in metastatic prostate cancer, and may portend resistance to docetaxel. CASCARA tested quadruplet therapy (ADT + cabazitaxel/carboplatin + abiraterone) in high-volume mCSPC, aiming to enhance PSA responses and decrease progression at 1 year. Methods: This phase 2 study enrolled 61 mCSPC patients with high-volume disease who received ADT plus cabazitaxel (20 mg/m2 q21d x 6) and carboplatin (AUC=4 q21d x 6) followed by abiraterone (1000 mg, plus prednisone 5 mg). Primary endpoint was freedom from PSA/radiographic progression at 1 year. Other endpoints included PSA50 response, freedom from PSA progression, and safety. Archival biopsies were retrospectively evaluated for HRR ( BRCA1/2, ATM, CHEK2, CDK12, BRIP1, RAD51B) mutations at a CLIA-certified lab. A sample size of 61 was determined using a Simon two-stage design (stage 1: 32 men, stage 2: 29 men) with a null hypothesis of a 1-year PSA/radiographic progression-free rate of 0.80 against a one-sided alternative of 0.92. Results: From 11/2019 to 06/2022, 61 men enrolled at 7 sites. Median age was 64 (range, 45–76) years; 21% were African American. Median baseline PSA was 8.9 (range, 0.1–1021) ng/mL. 44% of men had ECOG=1. 91% had Gleason sum 8–10. Prevalence of DNA alterations (50 evaluable pts) was 18% for HRR mutations, 38% for TP53 muts, 22% for ERG fusions, 10% for SPOP muts. Freedom from PSA/radiographic progression at 1 year was 77% (95% CI, 63–87%), and freedom from PSA progression at 1 year was 81% (95% CI, 67–90%). The PSA50 rate response was 97%. PSA ≤0.2 ng/mL at month-7, a surrogate for survival in other mCSPC studies, was 61%; PSA ≤4 ng/mL at month-7 was 82%. Outcomes according to mutation status are shown. AEs included 7% grade (Gr)-3/4 myelosuppression, 8% Gr-3/4 infections, 10% Gr-3 GI disorders, and 3% Gr-3 fatigue. There were 4 treatment-related discontinuations. Conclusions: Quadruplet therapy with ADT + cabazitaxel/carboplatin + abiraterone was well tolerated. At 1 year, 77% of pts were progression-free. PSA ≤0.2 ng/mL at month-7 was 61%, exceeding the historical month-7 PSA ≤0.2 ng/mL rate of 45% in CHAARTED–docetaxel arm. Further exploration of this quadruplet strategy in randomized phase III studies is warranted. Clinical trial information: NCT03934840 . [Table: see text]